DESCRIPTION 3 OVERALL PROGRAM CRITIQUE 3 PROGRESS DURING THE CURRENT FUNDING PERIOD 3 PROGRAM LEADERSHIP 3 PROGRAM AS AN INTEGRATED EFFORT 3 COLLABORATING INSTITUTIONS 4 PROJECT AND CORE SUMMARIES OF DISCUSSION 4 PROTECTION OF HUMAN SUBJECTS 5 VERTEBRATE ANIMALS 5 ADDITIONAL REVIEW CONSIDERATIONS 6 PROJECT 1: Mitochondrial Determination of Response to Targeted AML Therapies 7 PROJECT 2: Determination of the Mechanism of Lenalidomide Activity in Acute Myeloid Leukemia 8 PROJECT 3: Lysine Acetyltransferases in Myelopoiesis and Leukemia 10 PROJECT 4: Novel Epigenetic Approaches in AML 11 CORE A: Administrative Core 13 CORE B: Sample Processing and Analysis Core 14 CORE C: Biostatistics 16 CORE D: Clinical Research Support Core 16 COMMITTEE BUDGET RECOMMENDATIONS 19 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): The overall goal of this program is to develop more effective and less toxic therapies for the treatment of leukemia. Tremendous progress has been made in recent years in understanding the genetic and molecular basis of acute myeloid leukemia (AML), but progress towards improving outcomes for patients have been more limited. We will evaluate the efficacy and mechanistic basis for a set of novel therapeutic strategies for the treatment of AML. Specifically, we will investigate the modulation of apoptotic threshold in Project 1; inhibition of a specific ubiquitin ligase, CRL4-CRBN, by lenalidomide to induce cell cycle arrest, apoptosis, and differentiation; targeting lysine acetyltransferase activity to alter he function of transcription factors that are critical for AML biology in Project 3; and targeting key epigenetic regulators, BET bromodomain proteins and DOT1L, in Project 4. In addition to hypothesis-driven investigation of the biological mechanisms relevant to each therapeutic approach, we will investigate the therapeutic potential of these approaches using common assays and models. These therapeutic approaches will be investigated both individually and in combinations with existing therapies and each other. We will test molecules in vitro using dynamic BHS profiling, developed by Dr. Letai (Project 1) to examine the impact of candidate small molecules on apoptotic threshold. We will test molecules in vivo using both murine models developed by Dr. Bradner (Project 4) and primary human AML samples in xenograft models (Dr. Griffin, Core B). The most promising treatments will be brought forward to clinical trials in Core D. We will prospectively identify the subgroups most likely to respond by deep genetic and molecular characterization of AML samples used for pre-clinical and clinical studies. In aggregate, these studies will lead to the advancement of novel therapies for the treatment of AML, identification of genetic subgroups that are most likely to respond to novel treatments, and insights into the biological mechanisms of action for novel therapeutic strategies. RELEVANCE (See instructions): The overall goal of this program is to develop more effective and less toxic therapies for the treatment of leukemia. We will explore the targeting of epigenetic regulators, ubiquitin ligases, lysine acetyltransferases, and modulators of apoptotic threshold. Following pre-clinical studies in common model systems, the most promising therapies will be tested in clinical trials with deep molecular characterization of patient samples.